Single-cell transcriptomic profiling uncovers cellular complexity and microenvironment in gastric tumorigenesis associated with Helicobacter pylori.

[INTRODUCTION] Helicobacter pylori (H. pylori) infection is the main risk for gastric cancer (GC). However, the cellular heterogeneity and underlying molecular mechanisms in H. pylori-driven gastric tumorigenesis are poorly understood.

[OBJECTIVE] Here, we generated a single-cell atlas of gastric tumorigenesis comprising 18 specimens of gastritis, gastric intestinal metaplasia (IM) and GC with or without H. pylori infection.

[METHODS] Single-cell RNA sequencing (scRNA-seq) was performed. Immunofluorescence, immunohistochemistry and qRT-PCR analysis were applied in a second human gastric tissues cohort for validation. Bioinformatics analyses of public TCGA and GEO datasets were applied.

[RESULTS] Single-cell RNA profile highlights cellular heterogeneity and alterations in tissue ecology throughout the progression of gastric carcinoma. Various cell lineages exhibited unique cancer-associated expression profiles, such as tumor-like epithelial cell subset (EPC), inflammatory cancer-associated fibroblasts (iCAFs) and Tumor-associated macrophage (TAM). Notably, we revealed that the specific epithelial subset enterocytes from the precancerous lesion GIM, exhibited elevated expression of genes related to lipid metabolism, and HNF4G was predicted as its specific transcription factor. Furthermore, we identified differentially expressed genes in H. pylori-positive and negative epithelial cells, fibroblasts and myeloid cells were identified. Futhermore, H. pylori-positive specimens exhibited enriched cell-cell communication, characterized by significantly active TNF, SPP1, and THY1 signaling networks.

[CONCLUSIONS] Our study provides a comprehensive landscape of the gastric carcinogenesis ecosystem and novel insights into the molecular mechanisms of different cell types in H. pylori-induced GC.